esmo e-learning: overview on management of neuroendocrine

Overview on management of neuroendocrine tumor of

gastrointestinal tract

Ramon Salazar MD

Catalan Institute of Oncology

What are we talking about

� Derived from cells of the disseminated endocrine system � Antigens from both synaptic and endocrine vesicles1,2

� Historically classified based on embryonic origin3

� Foregut tumors

� Midgut tumors

� Hindgut tumors

� Today, primary tumor location is recommended for NET classification

� 5-7 % associated to MEN-1

1. Modlin IM, Öberg K, Chung DC, et al. Lancet. 2008;9:61-72. 2. Modlin IM, Kidd M, Latich I, et al. Gastroenterology. 2005;128:1717-1751. 3. NCCN. Neuroendocrine tumors, carcinoid tumors: management of recurrent or unresected disease. In: Practice Guidelines in Oncology. V.1. 2008. February, 2008.

Foregut• Thymus

• Esophagus

• Lung

• Stomach

• Pancreas

• Duodenum

Midgut• Appendix

• Ileum

• Cecum

• Ascending colon

Hindgut• Distal large bowel

• Rectum

Cell of origin belongs to the diffuse NE system present in various organs

� Characteristic secretory products in each cell type

Cell type Localization Products Tumors

Delta (D), enterochromaffin (EC), ghrelin (Gr), vasoactive

intestinal paptide (VIP) Entire GI tract

Somatostatin (D) serotonin/substance P/guanylin/melatonin

(EC)ghrelin (Gr), VIP

CarcinoidVipoma

Enterochromaffin-like (ECL) Gastric fundus Histamine Carcinoid

Gastrin (G)Gastric antrum and

duodenumGastrin Gastrinoma

I, motilin (M), secretin (S) Duodenum CCK, motilin, secretin CarcinoidK Duodenum/jejunum GIP Carcinoid

L, neurotensin (N) Small intestineGLP-1, PYY, NPY,

neurotensinCarcinoid

XStomach: fundus and

antrumAmylin

Alpha, beta, delta, pancreatic polypeptide (PP)

PancreasGlucagon, Insulin, somatostatin, PP

Glucagonoma, Insulinoma,

SomatostatinomaPPoma

CCK = cholecystokinin; GIP = gastric inhibitory peptide; GLP-1 = glucagon-like peptide 1; PYY = polypeptide YY (tyrosine,tyrosine); NPY = neuropeptide Y (tyrosine); PP = pancreatic polypeptide.

Modlin IM, Öberg K. A century of advances in neuroendocrine tumor biology and treatment. Hannover: Felsenstein CCCP; 2007.

Introduction (II)

� Ability to produce peptides that may lead to associated syndromes (functional vs. nonfunctional)1,2

� Functional or non-functional� Typical carcinoid syndrome (5HT, kinins, kalicrein, PG)

� 8.4% of carcinoids (15-30 % intestinal, 5% lung or thymic)

� Atypical carcinoid syndrome (histamine) � 5%-10% of lung- thymic sporadic gastric carcinoids

� Pancreatic syndromes

� General biochemical markers � IHC: CgA (chromogranin), synaptophyisin, ENE

� Serum and urine markers: CgA, 5HIAA

� High expression of SST Receptors (midgut>lung>thymus)

� Highly vascularized/angiogenic

� Therapeutic management� Low evidence levels/multidisciplinary treatment

Modlin IM, Öberg K, Chung DC, et al. Lancet. 2008;9:61-72. 2. Modlin IM, Kidd M, Latich I, et al. Gastroenterology. 2005;128:1717-1751.

Clinical Characteristics of pNET

Tumor typeProportio

n of pNETSigns and symptoms

Incidence of

metastases at

diagnosis

Insulinoma 17% Hypoglycemia, catecholamine excess 10%

Gastrinoma 15%Zollinger-Ellison syndrome (diarrhea/steatorrhea, gastroesophageal reflux, recurrent peptic ulcer)

60-90%

VIPoma 2%Hypokalemia, achlorhydria, watery diarrhea,

metabolic acidosis, hyperglycemia, hypercalcemia, flushing

80%

Glucagonoma 1%Diabetes mellitus, panhypoaminoaciduria, migratory

necrolytic erythema, thromboembolism, cachexia80-90%

Somatostatinoma

1%Diabetes mellitus, diarrhea/steatorrhea,

gallstones/gallbladder disease, hypochlorhydria, weight loss

60-70%

Non-functioning

60% May be first diagnosed due to mass effect 60%

1. Turaga KK, et al. CA Cancer J Clin. 2011;61(2):113-132 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors. V2.2010 3. Ehehalt F, et al. Oncologist. 2009;14(5):456-467.

SEER 9 registry: Age-adjusted incidence of GEP-NET over time in the US

All NETs and GEP-NETs

SEER, Surveillance, Epidemiology and End Results

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0Age

-adj

uste

d in

cide

nce

per

100,

000

2007

2005

2003

2001

1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

1977

1975

1973

Year of diagnosis

All NETs

GEP-NETs

Incidence of NET Is Increasing*

SEER = Surveillance, Epidemiology, and End Results (for malignant NET)

*Approximate 5-fold increase between 1975 and 2004

Approximate 7-fold increase also evident in Norwegian registry

Inci

denc

e pe

r 10

0,00

0

1.40

Year

1.20

1.00

0.80

0.60

0.40

0.20

0

NET Site

Lung

Colon

Small intestine

Rectum

Pancreas

Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

NET are more prevalent than gastric and pancreatic cancers combined

Yao JC, Hassan M, Phan A , et al. J Clin Oncol. 2008;26:3063-3072.

Column 1 = SEER data for 2005; all other columns = 29-year prevalence analyses based on SEER data for 2004.

Pre

vale

nce

Neoplasms

1,200,000

1,100,000

100,000

0

21,427Cases

28,664Cases

32,353Cases

65,836Cases

103,312Cases

1,168,000Cases

Molecular mechanisms involved in early tumorigenesis and tumor progression are poorly known

� Tumorigenesis

� No role for the «conventional» oncogenes and tumor suppressor genes known to be involved in epithelial carcinogenesis

� Several genes involved in syndromes of familial predisposition to endocrine tumors, behaving as tumor suppressor genes with a role in early tumorigenesis

� MEN-1, but also NF1, TSC1/2, VHL …

� Some candidate genes emerging

� PTEN ...

� Tumor progression

� Limited knowledge about the molecular mechanisms involved in local invasion and metastatic dissemination

Classification should answer threequestions

� How to identify an already malignant tumor ?

� How to identify a tumor which may eventually behave as a malignant tumor ?

� For malignant tumors, how to predict the rate of evolution ?

WHO classification, 2000

� Well differentiated endocrine tumors� Benign behavior

� Uncertain behavior

� Size (< or > threshold)

� Mitotic index or proliferation index (< or > threshold)

� MI <2 and Ki67 index ≤2%

� Angioinvasion

� Perineural invasion

� Functioning syndrome (except insulinoma)

If none:

Well differentiated endocrine tumor, benign behaviorIf at least one criteria:

Well differentiated endocrine tumor, uncertain behavior


� Presence of M1s: carcinoma� Well differentiated endocrine carcinomas

� Low grade of malignancy

� Morphology: poorly vs. well differentiated� Poorly differentiated endocrine carcinomas

� High grade of malignancy


� Neuroendocrine neoplasm, G1� Well differentiated morphology

� MI <2 and Ki67 index ≤2%

� Neuroendocrine neoplasm, G2� Well differentiated morphology

� MI: 2-20 and Ki67 index: 3-20%

� Neuroendocrine carcinoma� Small cell type

� Large cell type

� Mixed adeno-neuroendocrine carcinoma

Classifications

� Classification

� Grading

� Staging

� WHO� 2000

� 2010

� ENETS� ENETS 2006

� ENETS/UICC 2010

� TNM� ENETS (2006-2007)

� UICC (2010)

Known prognostic factors and therapy influence

� Location of primary tumor

� Extent of disease

� Tumor stage

� Degree of differentiation/proliferative index (PI)

� Tumor grade

� Patient age

� Performance status

Yao JC, et al. J Clin Oncol. 2008;26:3063–3072.

Distant metastases

1.0

0.8

0.6

0.4

0.2Sur

viva

l pro

babi

lity

0 12 24 36 48 60 72 84 96 108120

Time (months)

ColonLungPancreasRectumSmall bowel

Correlation of primary tumor site with survival

Primary location & prognosis

*Modlin et al. Cancer 2003, 97:934

M1 at Dx: SV 5 and (M1):

Carcinoids

Intestine 70% 55%

Colon 71% 20%

Appendix 10% 34%

Rectum 15% 30%

NEPT 76% 34%

Treatment of localized disease

� Surgical removal� Usually oncological

� Endoscopic resections are indicated for small non-invasive NET tumors in stomach, appendix and rectum

ENETS 2011 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors. Eds: R. Salazar, B. Wiedenmann, P Ruszniewski. Neuroendocrinology Vol. 95, No. 2, 2012, pp 71-177

Therapeutic options for patients with advanced NET

� Surgery� Curative or cytoreductive

� RF-ablation

� Liver Embolization

� PRRT/Receptor-targeted radiotherapy with somatostatin analogues

� Medical Therapy� Chemotherapy

� Somatostatin analogues

� Interferon-α

� New molecular targeted therapies


Surgery

� Localised disease

� Resection of the primary in M1� Yes, when feasible in the midgut carcinoids

� Not in the pancreatic NETs

� Surgery of the M1� SV 5 years >60% (>80% if R0)

� Without surgery: 30-50%

� When?

� R0 o <10% residual disease in liver M1

� OLT?

Norton JA et al.: Aggressive surgery for metastatic NET. Surgery 2003; 197: 29-37


Adjuvant treatment?

� There is no indication for adjuvant treatment following complete resection of localized disease

� There is no indication for adjuvant treatment following complete resection (R0-R1) of metastatic disease, either


Follow-up after resection

� Tumor-specific follow-up investigations are mainly based on imaging procedures and tumor markers and physical examination

� Sometimes endoscopic examinations are also warranted

� Specific tests and periodicity depends largely on location and extent or staging, and are addressed in a special paper within the 2009 Standards of Care ENETS Consensus Guidelines

R. Arnold et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Follow-Up and DocumentationNeuroendocrinology 2009;90:227–233

Is watch and wait policy a feasible option in low grade NETs?

� Yes, in those patients with G1 tumors without bulky disease it remains unclear if starting treatment early is better than waiting upon initial progression treatment

� Somatostatin analogues are usually the first systemic antiproliferative option in G1 tumors (PROMID data in midguts, retrospective data and expert opinion in other locations)

ENETS Consensus Guidelines for the Managementof Patients with Liver and Other Distant Metastases from Neuroendocrine Neoplasms of Foregut, Midgut, Hindgut, and Unknown Primary. M. Pavel, R. Salazar et al. Neuroendocrinology Vol. 95:157–176

Thermal radiofrequency ablation:Literature review

� RFA efficacy and indications1

� Radiological complete response > 80%

� Response duration 12 month (appearance of new M1)

� <6 lesions, <4 cm (not if close to liver hilum or large vessels)

� Feasible with higher number and size2

� Symptoms response 71–95% & bioch response 65%

� Response duration 8–10 months

� Surgery and RFA radical or debulking3

� <10 lesions, <4 cm (RF)

� R0: 12 of 23 (52%) & symptom response 12/17 (71%)

� Cost and morbidity are low

1.Berber et al. 2002; 2.Vogl et al. Eur J Radiol, 72 (2009) 517–528;3.Eriksson et al. World J Surg (2008) 32:930

Liver M1s mainly irrigatedthrough hepatic arteries

Embolization producesischemia and necrosis

David C Metz. Gastroenterology. 2008 November; 135(5): 1469–1492Images courtesy of Erasmus MC, Rotterdam, The Netherlands.

Hepatic arterial (chemo) embolization

Hepatic arterial (chemo) embolization. Literature Review

� Radiological responses rates: 32%-82%

� Symptomatic responses rates: 60–95%

� Biochemical responses rates: 50–90%

� Progression free survival: 18-24 months

� Complications

� Frequent post-embolization syndrome (pain, fever, transaminase elevation, N/V)

� Colecystitis, HTA, infections

T.J. Vogl et al. Eur J Radiol, 72 (2009) 517–528

HAE versus HACE: Efficacy results progression free survival

HACE HAE P

Median PFS 19.2 [16.1-26.8] 23.6 [12.7-NA]

2-year PFS rates 38% 44% 0.90

HACE

HAE

months

F. Maire et al. ENETS Congress 2011. Copyright granted by S. Karger AG

Medical treatment & PRRT

� Interferon alpha

� Systemic chemotherapy

� Molecular targeted therapy

� Somatostatin analogs

� Peptide receptor targeted therapy (PRRT)

� New molecular targeted therapies

� Sunitinib (sutent vs. placebo Phase III)

� Everolimus (RADIANT trials)

Regimen PhaseNo. of Pts

Tumour RR (%)

Median OS (mos)

PFS (mos) Year

Prospective Studies

STZ + 5-FU III 42 63 26— 19801

STZ III 42 36 16.4

STZ + DOX III 36 69 26.4

— 19922STZ + 5-FU III 33 45 16.8

CLZ III 33 30 18

STZ = streptozocin; 5-FU = 5-fluorouracil; DOX = doxorubicin; CLZ = chlorozotocin; DTIC = dacarbazine; RR = response rate; NR = not reported; NR* = not reached.

Combination Regimens:Cytotoxic Chemotherapy Metastatic pNET

1. Moertel CG, et al. N Engl J Med. 1980;303:1189-1194; 2. Moertel C, et al. N Engl J Med. 1992;326:519-523; 3. Ramanathan RK, et al. Ann Oncol. 2001;12:1139-1143;4. Kulke MH, et al. J Clin Oncol. 2006;24:401-406; 5. Kulke MH, et al. J Clin Oncol. 2006;24(suppl). Abstract 4044; 6. Kulke MH, et al. ASCO Gastrointestinal Cancers Symposium 2010.Abstract 223; 7. Kouvaraki MA, et al. J Clin Oncol. 2004;22:4762-4771; 8. Turner NC, et al. Br J Cancer. 2010;102:1106-1112; 9. Kulke MH, et al. Clin Cancer Res. 2009; 15:338-345; 10. Ekeblad S, et al. Clin Cancer Res. 2007;13:2986-2991; 11.Strosberg JR, et al. Cancer. 2011;117:268-275.

*Not reached at median f/u of 26 months.

Retrospective Studies

STZ + DOX + 5-FU — 84 39 37 18 20047

STZ + 5-FU + Cisplatin 47 38 31.5 9.1 20108

Temozolomide (diverse regimens) — 53 34 35.3 13.6 20099

Temozolomide (single agent) — 12 14 — — 200710

Temozolomide + capecitabine — 30 70 — 18 201011

DTIC II 50 34 19.3 — 20013

Temozolomide + thalidomide II 11 45 NR* NR* 20064

Temozolomide + bevacizumab II 18 24 — — 20065

Temozolomide + everolimus I/II 24 35 — — 20106

Temozolomide in pancreatic neuroendocrine carcinoma

Strosberg JR, et al. Cancer 2011;117:268–75

Capecitabine: 750 mg/m2 x 2 x tgl. (days 1–14)Temozolomide: 200 mg/m2 x 1 (days 10–14); every 28 days

n=30: 22 NF; 2 gastrinoma; 2 insulinoma; 2 VIPoma; 1 glucagonoma; 1 gastrinoma/glucagonoma

70% PR(RECIST)

Median PFS:18 months

Retrospective analysis

G3–4 adverse events (12%): anaemia, thrombocytopenia, elevation of liver enzymes

100

80

60

40

20

0

–20

–40

–60

–80

–100

Progressive Disease

Partial Response




� Molecular targeted therapy� Somatostatin analogs


� New molecular targeted therapies� Sunitinib (sutent vs. placebo Phase III)


NET express multiple sstr subtypes

Prevalence on NET type1:

Carcinoid 76% 80% 43% 68% 77%

Gastrinoma 79% 93% 36% 61% 93%

Insulinoma 76% 81% 38% 58% 57%

Non-functioning islet cell tumor 58% 88% 42% 48% 50%

Inhibitory effect2,3:

Hormone secretion + + +

Proliferation + + + +

Induction of apoptosis + +

1. Hofland LJ, et al. J Endocrinol Invest 2003;26:8–13. 2. Ferrante E, et al. Endocr Relat Cancer 2006;13:955–962. 3. Susini C & Buscail L. Ann Oncol 2006;17:1733–1742.

sstr2 is the most prevalent

Octreotide LAR 30 mg extends TTP in patients with functioning and non-functioning tumors

0

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 900

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90

Based on the per protocol analysis

P=0.0008; HR=0.25 [95% CI: 0.10–0.59]

Pro

port

ion

with

out p

rogr

essi

on

P=0.0007; HR=0.23 [95% CI: 0.09–0.57]

Pro

port

ion

with

out p

rogr

essi

on

Patients with non-functioning tumors

Patients with functioning tumors

Time (months)Time (months)

Octreotide LAR 30 mg: 17 pts / 11 eventsMedian TTP 14.26 months

Placebo: 16 patients / 14 eventsMedian TTP 5.45 months

Octreotide LAR 30 mg: 25 pts / 9 eventsMedian TTP 28.8 months

Placebo: 27 patients / 24 eventsMedian TTP 5.91 months

Rinke A, Barth P, Wied M, et al. J Clin Oncol. 2009;27:4656-4663.

Peptide receptor radionuclide therapy (PRRT)in the Treatment of pNET

• Used to treat patients with advanced pNET1

• Clinical evidence is limited and based on:1-3

� Case reports

� No prospective randomized trials

� No survival benefit report

� Limited availability and access4

� Toxicity issues4

1. Kwekkeboom DJ, et al. J Clin Oncol. 2005;23:2754-2762; 2. Waldherr C, et al. J Nucl Med. 2002;43:610-616;3. Valkema R, et al. Semin Nucl Med. 2002;32:110-122; 4. Kwekkeboom DJ, et al. J Clin Oncol. 2008;26:2124-2130.

Tumor responses in patients with GEP-NET treated with different radio labeled SSA

Kwekkeboom DJ et al., J Clin Oncol 2010

Lack of randomized trials

Overview of Reported PRRT Survival Data in Patients with NET

Ligand Phase Patient typeNo. of Pts

Tumour RR(PR/CR)

Median OS (mos)

PFS (mos)

Year

Prospective Studies

90Y-Edotreotide II Carcinoid 90 4.4%* 26.9 16.3 20101

90Y-DOTATOC IIpNET, Intestinal NET, Bronchial NET, Unknown

4124%

(36% pNET)

2yr = 76 +16% — 20012

90Y-DOTATOC II GEP-NET, Bronchial NET 3923%

(38% pNET)— — 20023

111In-DTPA-octreotide

ll GEP-NET 278%

(n=26)18 — 20024

111In-DTPA-octreotide

I

Carcinoid, Insulinoma, Glucagonoma, Gastrinoma, VIPoma, Pheochromocytoma, Sarcoma, Glomus tumour, medullary TC

40 <53% — — 20025

1. Bushnell DL Jr, et al. J Clin Oncol. 2002;28:1652-1659; 2. Waldherr C, et al. Ann Oncol. 2001;12:941-945; 3. Waldherr C, et al. J Nucl Med. 2002;43:610-616; 4. Anthony LB, et al. Semin Nucl Med. 2002;32:123-132; 5.Valkema R, et al. Semin Nucl Med. 2002;32:110-122; 6. Kwekkeboom DJ, et al. J Clin Oncol. 2005;23:2754-2762; 7. Kwekkeboom DJ, et al. J Clin Oncol. 2008;26:2124-2130.

Retrospective Studies

177-Lu-DOTATATE — Carcinoid, pNET, Unknown, Gastrinoma, Insulinoma

131 28% — >36 (TTP)

20056

177-Lu-DOTATATE — Carcinoid, NF pNET, Unknown, Gastrinoma, Insulinoma, VIPoma

310† 30% 46 32‡ 20087

*Unconfirmed;†Evaluable patient population; ‡Also reported as 33 months.




� Molecular targeted therapy� Somatostatin analogs


� New molecular targeted therapies� Sunitinib (sutent vs. placebo Phase III)


Medical treatment of advanced disease

� In 2011, results from 2 randomized placebo-controlled phase III trials demonstrated benefit of novel therapies in patients with advanced pNET

� Sunitinib (multitargeted tyrosine kinase inhibitor [VEGFR, PDGFR]) vsplacebo (Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med 2011;364:501-513)

� Everolimus (inhibitor of mammalian target of rapamycin [mTOR]) vsplacebo (Yao JC, Shah MH, Ito T, et al. N Engl J Med 2011;364:514-523)

New molecular targets

� SST receptors

� High expression of other druggable oncogenic pathways

� PI3K/PAKT/MTOR� Mutations/amplification… of oncogenes

and tumor suppressor genes (PTEN, TSC1/2)

� Mutations in 14% of the pNETs tumors

� Extraordinary vascularization (angiogenesis)� High expression of VEGF and VEGFR

� High expression of PDGFR

� Preclinical proof of concept

Yuchen Jiao et al, Science 2011 Jan; Terris B, Scoazec JY, Rubbia L, et al.: Expression of vascular endothelial growth factor in digestive neuroendocrine tumors. Histopathology 32:133-8, 1998; Parangi, S., Dietrich, W., Christofori, G., Lander, E., & Hanahan, D. (1995). Tumor suppressor loci on mouse chromosomes 9 and 16 are lost at distinct stages of tumorigenesis in a transgenic model of islet cell carcinoma. Cancer Res., 55:6071-6076. Casanovas, O., Hager, J., Chen, M., & Hanahan, D. (2005). Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis. Oncogene, 24, 6597-604; Calender A., Deregulation of genetic pathways in neuroendocrine tumors; Atlas Genet CytogenetOncol Haematol December 2001.

Rationale for mTOR Inhibition in NET

� mTOR is a central regulator of growth, proliferation, cellular metabolism, and angiogenesis1-3

� mTOR pathway activation observed in genetic cancer syndromes associated with pNET (TSC2, NF1, VHL)4

� Everolimus has demonstrated antitumour activity in NET in preclinical and clinical phase II and phase III studies7-9

� Mutations of mTOR pathway components TSC, PTEN, PIK3CA seen in 14% sporadic pNET; ↓PTEN and ↓TSC2 expression associated with poor prognosis5-6

1.O’Reilly T, et al. Transl Oncol. 2010;3(2):65-79; 2.Meric-Bernstam F, et al. J Clin Oncol. 2009;27:2278-2287; 3.Faivre S, et al. Nat Rev Drug Disc. 2006;5:671-688; 4.Yao J, et al. Pancreatic Endocrine Tumours. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 8th Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:1702-1721; 5.Missialgia E, et al. J Clini Oncol. 2010;28: 245-255; 6.Jiao Y, et al. Science. 2011;331:1199-203; 7.Yao J, et al. J Clin Oncol. 2008;26:4311-4318.; 8.Yao J, et al. J Clin Oncol. 2010;28:69-76; 9.Yao J, et al. N Engl J Med. 2011; 364:514-523.

TSC2 = tuberous sclerosis 2; NF1 = neurofibromatosis type I; VHL = von Hippel-Lindau disease

mTOR pathway and sporadic pNET

0 5 10 15 20

High level TSC2Low level TSC2

Ove

rall

surv

ival

Time (years)

1.0

0.5

0 5 10 15 20

High level TSC2Low level TSC2

Pro

gres

sion

-fre

e su

rviv

al

Time (years)

1.0

0.5

Time (years)0

High level PTENLow level PTEN

Pro

gres

sion

-fre

e su

rviv

al

1.0

0.5

5 10 15 20

Missiaglia E, Dalai I, Barbi S, et al. J Clin Oncol. 2010;28:245-255.

TSC2 expression

PTEN expression

Rationale for combining everolimus and octreotide LAR

� mTOR is a central regulatorof growth, proliferation, metabolism, and angiogenesis1-3

� Everolimus inhibits mTOR3

� Octreotide downregulatesIGF-1, an upstream activator of the PI3K/AKT/mTORpathway4

� Everolimus + octreotide LAR has shown activity in a phase II trial5

1.O’Reilly T, et al. Transl Oncol. 2010;3(2):65-79. 2.Meric-Bernstam F, et al. J Clin Oncol. 2009;27:2278-2287. 3.Faivre S, et al. Nat Rev Drug Disc. 2006;5:671-688. 4.Susini C, et al. Ann Oncol. 2006;17:1733-1742. 5.Yao JC, et al. J Clin Oncol. 2008;26:4311-4318.

Growth andproliferation

IGF-1R

IGF-1

mTORinhibitormTORinhibitor

IGF-1R

IGF-1 VEGF

VEGFR

mTOR

Angiogenesis

Survival

Metabolism

VHL

TSC1/2

PTEN

NF1

X X XX

↓signaling↓signaling

Caspase 8p53Bax

Caspase 8p53Bax

↓secretion↓ligands↓secretion↓ligands

SHP1

sstr1-5sst analogue

NFcbNFcb

Ca2·

K+

RADIANT-2: Study Design

� Patients with advanced NET (non-pancreatic) and history of flushing and/or diarrhea (N = 429)� Advanced well or

moderately differentiated

� Radiologic progression ≤12 months

� Prior antitumor therapy allowed

� WHO PS ≤2

� No Stratification

Everolimus 10 mg/day + Octreotide LAR 30 mg/28 days

n = 216

Placebo + Octreotide LAR 30 mg/28 days

n = 213

Treatment until disease progression

1:1

Multiphasic CT or MRI performed every 12 weeks

Crossoverat time of disease progression

Phase III, randomized, double-blind, placebo-controlled, multicenter trial

Yao J, et al. 2011 Gastrointestinal Cancer Symposium; January 20-22, 2011; San Francisco, CA, USA. Abstract 158.

Primary endpoint: Progression-free survival by central adjudicated review Secondary endpoints: OS, ORR, biomarkers, safety, PKs

RANDOMIZE

MTOR inhibitors in GEP-NET Early clinical trials

AgentDrug company

Target & mechanism

Type of trialResponse

rateReference

Temsirolimus(CCI-779) Wyeth

MTOR Protein kinase

inhibitor

Phase IICarcinoidIslet cell

4.8 %6.7 %

(Duran et al., 2006)

Everolimus(RAD001) Novartis

MTOR Protein kinase

inhibitor

Phase II (MDACC)CarcinoidPancreatic

Pancreatic(Radiant 1)

+/- octreotide

17 %27 %

6.8 %

(Yao et al, JCO 2009)

(Yao et al, JCO 2009)

RADIANT-2: Baseline characteristics

Everolimus + Oct LAR(n = 216)

Placebo + Oct LAR(n = 213)

Median age, years (range) 60 (22-83) 60 (27-81)

Male:Female (%) 45:55 58:42

WHO PS (%)

0 55 66

½* 39/6 29/5

Primary site (%)

Small intestine 51 53

Lung* 15 5

Colon 6 7

Pancreas 5 7

Liver 3 5

Prior somatostatin analogues 80 78

Prior systemic antitumour therapies 46 39

Chemotherapy* 35 26

Immunotherapy 13 9

Targeted therapy 7 8

Other 10 13

* Statistically significant for imbalance P<.05. One missing PS in placebo arm.Yao J, et al. 2011 Gastrointestinal Cancer Symposium; January 20-22, 2011; San Francisco, CA, USA. Abstract 158.

RADIANT-2: PFS by local investigator review

Number of patients still at riskE + OP + O

216213

199201

167159

129121

119114

10092

8175

7472

6864

6256

5150

4041

3227

2421

1811

1110

44

21

10

00

E + O = Everolimus + Octreotide LARP + O = Placebo + Octreotide LAR

Per

cent

age

even

t-fr

ee

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

Time (months)

Kaplan-Meier median PFSEverolimus + Octreotide LAR: 12.0 monthsPlacebo + Octreotide LAR: 8.6 months

Hazard ratio = 0.78; 95% CI [0.62-0.98]P value = .018

Total events = 284Censoring timesE + O (n/N = 128/216)P + O (n/N = 156/213)

Pavel M, Hainsworth J, Baudin E, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA8

P value is obtained from the one-sided log-rank testHR is obtained from unadjusted Cox model

RADIANT-2: PFS by central review*

Time (months)Number of patients still at riskE + OP + O

216213

202202

167155

129117

120106

10284

8172

6965

6357

5650

5042

4235

3324

2218

1711

119

43

11

10

00

*Independent adjudicated central review committeeP value is obtained from the one-sided log-rank testHR is obtained from unadjusted Cox model

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

Per

cent

age

even

t-fr

ee

Kaplan-Meier median PFSEverolimus + Octreotide LAR: 16.4 monthsPlacebo + Octreotide LAR: 11.3 months

Hazard ratio = 0.77; 95% CI [0.59-1.00]P value = .026 (pre-specified boundary = .0246)


Total events = 223Censoring timesE + O (n/N = 103/216)P + O (n/N = 120/213)

E + O = Everolimus + Octreotide LARP + O = Placebo + Octreotide LAR

Subgroups (N) HR

Median PFS (mos.)

E + O P + OCentral review *(429) 0.77 16.4 11.3Local investigator review (429) 0.78 12.0 8.6Age group

<65 years (286) 0.78 19.2 13.0≥65 years (143) 0.75 13.9 11.0

Gender Male (221) 0.85 13.7 13.0Female (208) 0.73 17.1 11.1

WHO Performance StatusWHO = 0 (251) 0.67 19.3 13.6WHO > 0 (176) 0.81 13.8 8.3

Tumor histology gradeWell diff. (341) 0.74 18.3 13.0Moderately diff. (68) 0.82 13.7 7.5

Primary tumor siteSmall intestine (224) 0.77 18.6 14.0Lung (44) 0.72 13.6 5.6Colon (28) 0.39 29.9 13.0Other (132) 0.77 14.2 11.0

Prior long-acting SSAYes (339) 0.81 14.3 11.1No (90) 0.63 25.2 13.6

Prior chemotherapyYes (130) 0.70 13.9 8.7No (299) 0.78 19.2 12.0

*Independent adjudicated central reviewHR = Everolimus + Octreotide/Placebo + OctreotideUnstratified Cox model was used to obtain hazard ratio

Hazard ratio

Favors E + O Favors P + O

0 10.4 0.8 1.4

Pavel M, Hainsworth J, Baudin E, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA8

Subgroup PFS analysis

Baudin E, Wolin E, Catellano D, et al. Presented at: 8th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstr C11.

5-HIAA, 5-hydroxyindoleacetic acid

Best response, n (%)

Everolimus + octreotide

LARn=140

Placebo +octreotide

LARn=141

≥50% reduction from baseline or normalization

85 (60.7) 66 (46.8)

Stable disease 53 (37.9) 72 (51.1)

Progressive disease 2 (1.4) 3 (2.1)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Fol

d ch

ange

from

bas

elin

e

0 2 3 4 5 6 7 8 9 10 11 12

00

118119

122120

102117

99108

9197

9289

7274

7072

6675

6055

5449

Cycle:

E+O patients, n:P+O patients, n:

Everolimus + octreotidePlacebo + octreotide

Everolimus + octreotide LARimproves control of 5-HIAA levels

RADIANT-2: Treatment-related adverse events

� Safety profile was similar to the known safety profile of everolimus + octreotide LAR

� Most frequently reported all-grade treatment-related AEs with everolimus + octreotide LAR were stomatitis (62%), rash (37%), fatigue (31%), diarrhea (27%), nausea (20%), and infections (20%)

� Grade 3/4 AEs (≥5%) in the everolimus + octreotide LAR arm included stomatitis (7%), fatigue (7%), diarrhea (6%), infections (5%), thrombocytopenia (5%), and hyperglycemia (5%)


Everolimus 10 mg/d +best supportive care*

n = 207

RADIANT-3: Study Design

� Patients with advanced pNET (N = 410)� Advanced well or

moderately differentiated

� Radiologic progression ≤12 months

� Prior antitumor therapy allowed

� WHO PS ≤2

� Stratified by:� WHO PS

� Prior chemotherapy

Placebo +best supportive care*

n = 203

Multiphasic CT or MRI performed every 12 weeks

Treatment until disease progression

Crossover at disease progression

*Concurrent somatostatin analogues allowed

RANDOMIZE

Phase III, double-blind, placebo-controlled trial

Primary endpoint: Progression-free survival by investigator reviewSecondary endpoints: OS, ORR, biomarkers, safety, pharmacokinetics (PK)

Yao J, et al. N Engl J Med. 2011;364:514-523.

1:1

RADIANT-3: Baseline characteristics

Everolimus (n = 207) Placebo (n = 203)

Median age, years (range) 58 (23-87) 57 (20-82)

Male:Female (%) 53:47 58:42

WHO PS (%)

0 / 1 / 2 67 / 30 / 3 66 / 32 / 3

Number of disease sites (%)

1 25 31

2 41 32

≥3 34 38

Histologic grade (%)

Well differentiated 82 84

Moderately differentiated 17 15

Unknown 1 1

Prior treatment (%)

Somatostatin analogues 49 50

Chemotherapy 50 50

Radiotherapy 23 20


RADIANT-3: PFS by investigator review

P value is obtained from stratified one-sided log-rank testHazard ratio is obtained from stratified unadjusted Cox model

Number of patients still at risk

Everolimus

Placebo

207203

189177

15398

12659

11452

8024

4916

367

284

213

102

61

21

01

Kaplan-Meier median PFS

Everolimus: 11.0 monthsPlacebo: 4.6 months

HR = 0.35; 95% CI [0.27-0.45]P value: <0.0001

01

00

Time (months)

100

80

Eve

nt-f

ree

(%)

Censoring TimesEverolimus (n/N = 109/207)Placebo (n/N = 165/203)

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

PFS rate (18 months) Everolimus: 34.2% Placebo: 8.9%


RADIANT-3: PFS by central review*

*Independent adjudicated central review committeeP-value obtained from stratified 1-sided log-rank testHR obtained from stratified unadjusted Cox model


Everolimus: 11.4 monthsPlacebo: 5.4 months

HR = 0.34; 95% CI (0.26–0.44)P<0.001

No. of patients still at riskEverolimusPlacebo

207203

187180

15299

12660

11752

8122

4912

365

273

221

101

61

20

00

Time (months)

100

80

Eve

nt-f

ree

(%)

Censoring timesEverolimus (n/N = 95/207)Placebo (n/N = 142/203)

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.

RADIANT-3: Response rates

RECIST 1.0Objective tumor responses

Everolimus 10 mg n = 207 n (%)

Placebon = 203n (%)

Complete response (CR) 0 0

Confirmed Partial response (PR) 10 (5) 4 (2)

Stable disease (SD) 151 (73) 103 (51)

Progressive disease (PD) 29 (14) 85 (42)

Unknown 17 (8) 11 (5)

2-sided P-value for treatment difference* P<0.001

Disease control rate (CR + PR +SD) 161 (78) 107 (53)

*Wilcoxon 2-sample test

Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.

RADIANT-3: Overall survival analysis

148 placebo patients crossed over at time of progression to receive everolimus

1. Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523; 2. Yao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9.

100

80

60

40

20

0

Eve

nt-f

ree

(%)

No. of patients still at risk

Censoring Times1

Everolimus (n/N = 51/207)Placebo (n/N = 50/203)

EverolimusPlacebo

207203

Kaplan Meier medianEverolimus: NA monthsPlacebo : NA months

Hazard Ratio: 1.0595% CI [0.71,1.55]

Log-rank p-value = 0.59

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Time (months)

203199

195195

188183

181174

162160

122129

97109

7487

5363

3842

2623

916

57

28 30

03

01

32

00

Subgroup PFS analysis

Subgroups (N) HR

Median PFS (mos.)

E PInvestigator review (410) 0.35 11.0 4.6Central review* (410) 0.34 11.4 5.4Prior chemotherapy

Yes (189) 0.34 11.0 3.0No (221) 0.41 11.1 5.5

WHO Performance Status0 (279) 0.39 13.8 5.41 or 2 (131) 0.30 8.3 3.0

Age Group<65 years (299) 0.39 11.0 4.5≥65 years (111) 0.36 11.1 4.9

GenderMale (227) 0.41 11.0 4.6Female (183) 0.33 11.0 3.3

RaceCaucasian (322) 0.41 10.8 4.6Asian (74) 0.29 19.5 3.8

RegionAmerica (185) 0.36 11.0 4.6Europe (156) 0.47 10.8 4.6Asia (69) 0.29 19.5 2.9

Prior long-acting SSAYes (203) 0.40 11.2 3.7No (207) 0.36 10.8 4.9

Tumor gradeWell diff. (341) 0.41 10.9 4.6Moderately diff.(65) 0.21 16.6 3.0

*Independent adjudicated central reviewE = Everolimus 10 mg PO daily; P = Placebo

Hazard Ratio

Favors Everolimus Favors Placebo

0 10.4 0.8

Yao J, Shah M, Ito T, et al. NEJM 2011; 364:514-23.

RADIANT-3: Treatment-related adverse events

� Everolimus toxicities were similar to those seen in other tumor types

� Most frequently reported all-grade treatment-related AEs with everolimus were stomatitis (64%), rash (49%), diarrhea (34%), fatigue (31%), and infections (23%)

� Grade 3/4 AEs (≥5%) in the everolimus arm included stomatitis (7%), anemia (6%), and hyperglycemia (5%)


Everolimus in NETs: Summary

� RADIANT trial program successfully enrolled 999 patients� This clearly demonstrates large trials are possible in this patient setting

� Everolimus represents a new treatment option for patients with advanced pancreatic progressive NET and could be also useful in nonpancreatic NETs

� For the first time, large phase III randomized trials have been completed in NET� These studies have added new therapeutic options for patients with

advanced NET

� Everolimus and sunitinib have recently been approved for the treatment of advanced pNET

Involvement of VEGF in the angiogenesis of NET

� NET are highly vascularized and express VEGF and VEGF-R1

� VEGF expression correlates with decreased PFS duration2

� Angiogenesis inhibitors that target VEGF have been shown to have preclinical & clinical activity in NET3

IGF-1

HER2

EGF

Metabolism

TSC1/2

PTEN

Aberrantly activatedPI3K/AKT/mTORpathway

TumorCell

Growth andproliferation

IGF-1R

mTORERK

RAF

MEK

EGFR

PDGFR

PDGF

Angiogenesis

EndothelialCell

VEGFVEGF

VEGFRVEGFR

Survival

Angiogenicfactors

1.Yao JC, Phan AT, Hoff PM, et al. J Clin Oncol. 2008;26(8)1316-1323. 2. Phan AT, Wang L, Xie K, et al. J Clin Oncol. 2006;24(18s suppl):abstract 4091. 3. Eriksson B. Curr Opin Oncol. 2010;22(4):381-386.

Angiogenesis

Angiogenesis inhibitors

Agent (s) Target (s) N TumorORR ,

%Outcomes Comments

Bevacizumab +

octreotide1VEGF 22 Carcinoid 18 16.5 months (PFS) –

Sunitinib2 VEGFR, PDGFR, RET, FLT3

41

66

Carcinoid

Pancreatic NET

2

17

10.2 months (TTP)

7.7 months (TTP)–

Sorafenib3 VEGFR, PDGF, Raf

50

43

Carcinoid

Pancreatic NET

7

17

8 months (PFS)

12 months (PFS)–

Vatalanib4

VEGFR, PDGFR 11 GEP NET 0 Not reported Ongoing

Pazopanib5 VEGFR, PDGFR,30

30

Carcinoid

Pancreatic NET–

–

–Ongoing

Motesanib6 VEGFR, PDGFR, RET

44 LGNET – – Suspended

Atiprimod7

Unclear 25 LGNET 0 – Completed

Bevacizumab +

2-methoxyestradiol8VEGF 31 Carcinoid 0 – Ongoing

Sunitinib9 VEGFR, PDGFR, RET, FLT3

74 Pancreatic NET–

11.1 months (PFS) Terminated

1. Yao JC, et al. J Clin Oncol 2008:26;1316-23. 2. Kulke MH, et al. J Clin Oncol 2008:26;3403-10.3. Hobday TJ, et al. J Clini Oncol 2007;25:[abstract 4504]. 4. Anthony L, et al. J Clin Oncol 2008;26:[abstract 14624].5. NCT00454363. Available from www.clinicaltrial.gov. 6. NCT00427349. Available from www.clinicaltrial.gov.7. Sung MW, et al. J Clin Oncol 2008;26:[abstract 4611]. 8. NCT00328497. Available from www.clinicaltrial.gov.9. Raymond E, et al. Oral presentation at the World Congress on Gastrointestinal Cancers. 2009:[abstract O-0013].

ORR = overall response rate; PDGF = platelet-derived growth factor; PDGFR = PDGF receptor; LGNET = low-grade NET.

Phase II bevacizumab in GEP-NETs

JC Yao et al., J Clin Oncol 2008; 26: 1316-1323

44 patients with M1 carcinoids on

octreotide

Bevacizumab15 mg/kg i.v. q 3 wks

X 18 weeks

Response = 4 (18%)

PFS 95%

PEG interferon alpha-2b

0.5 mcg/kg sc once per week X 18 weeks

Response = 0PFS 68% (P=0.01)

Bevacizumab +

PEG Interferon alpha –2b

S0518 bevacizumab Phase III trial in GEP-NET

(N=283)

Octreotide plus interferon

Octreotide plus bevacizumab

On-going trial

Sunitinib vs. placebo in advanced pNET

� Eligibility criteria� Well-differentiated

malignant pNET

� Disease progression ≤12 months

� Not amenable to curative treatment

� 340 patients planned

� 171 patients enrolled

� No stratificationPrimary endpoint: PFS by investigator review

Secondary endpoints: OS, overall response rate (ORR), time to recurrence, duration of response, safety, and patient-reported outcomes

Sunitinib 37.5 mg/day orallyn = 86

Continuous daily dosing*

RANDOMIZE

Placebo*n = 85

1:1

*With best supportive careSomatostatin analogues were permitted

Raymond E, et al. N Engl J Med. 2011;364:501-513.

Crossover at early

termination

Phase III, randomised, placebo-controlled, double-blind trialIDMC early unplanned analysis

Study A6181111: Baseline characteristics

Sunitinib(N = 86)

Placebo(N = 85)

Median age, yr (range) 56 (25–84) 57 (26–78)

Male, n (%) 42 (49) 40 (47)

Female, n (%) 44 (51) 45 (53)

ECOG performance status, n (%)

0 53 (62) 41 (48)

1 33 (38) 43 (51)

2 0 1 (1)

Number of disease sites, n (%)

1 30 (35) 23 (27)

2 31 (36) 26 (31)

≥3 24 (28) 35 (41)

Presence of distant metastases, n (%)

Any, including hepatic 82 (95) 80 (94)

Extrahepatic 21 (24) 34 (40)

Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.

Sunitinib Phase III –PFS by investigator review

1.0

0.8

0.6

0.4

0.2

0

Pro

port

ion

of p

atie

nts

0 5 10 15 20 25


Sunitinib:Placebo:

HR = 0.418; 95% CI [0.263-0.662]P value = .0001

86 39 19 4 0 085 28 7 2 1 0

Number at risk

Sunitinib

Placebo

Time (months)

Events

Sunitinib (n/N = 30/86)Placebo (n/N = 51/85)


11.4 months; 95% CI [7.4-19.8]5.5 months; 95% CI [3.6-7.4]

Study A6181111: Response rates

RECIST 1.1*

Objective tumor responses1

Sunitinib

(n=86)

Placebo

(n=85)

Best tumor response, n (%)

Complete response

Partial response

Stable/no response

Objective progression

Not evaluable

2 (2)

6 (7)

54 (63)

12 (14)

12 (14)

0

0

51 (60)

23 (27)

11 (13)

Objective response rate (95% CI) 9.3% (3.2–15.4) 0

P=0.007

Median time to response, mo (range) 3.1 (0.8–11.1) -

Duration of response, mo (range) 0.9 to >15.0 -

1. Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al. Eur J Cancer 2009;45:228-247.

*Confirmation not required when PFS is primary endpoint2

Sunitinib: Treatment-related adverse events

� Sunitinib toxicities were similar to those seen in other tumor types

� Most frequently reported all-grade adverse events (AEs) with sunitinib were diarrhea (59%), nausea (45%), asthenia (34%), vomiting (34%), and fatigue (33%)

� Grade 3/4 AEs (≥5%) in the sunitinib arm included neutropenia (12%), hypertension (10%), palmar-plantar erythrodysesthesia (6%), diarrhea (5%), asthenia (5%), fatigue (5%), and abdominal pain (5%)


Sunitinib: Summary

� Sunitinib enrolled 171 patients with advanced pNET

� Sunitinib provided a 5.9-month improvement in median PFS compared with placebo in patients with advanced pNET

� Unplanned early termination compromised robustness of the trial design making the estimation of the magnitude of benefit and statistical significance uncertain

� Approved in the EU and US for the treatment of progressive well-differentiated pNET in patients with unresectable locally advanced or metastatic disease

� Toxicities were consistent with those observed in other trials of sunitinib

Conclusions

� New classifications but the crucial information remains the same

� Surgery and loco regional therapy whenever feasible

� Chemo and interferon no change (chemo for pNETS, IFN low evidence highly toxic)

� Octreotide and lanreotide are very efficacious for syndrome control� Octreotide also prevents tumor progression in midgut tumors

� PRRT for octreoscan + is a compassionate use alternative

� Everolimus and sunitinib have emerged as validated treatment alternatives for advanced NETs

� Sunitinib and everolimus have meaningful improvement in median PFS compared with placebo in pNETs with acceptable safety

� Everolimus may also become a new therapeutic alternative in advanced GI NETs

Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.

Advanced NET

Low proliferationKi-67 <2% or GI NET

pNET> Ki-67

Biological therapy(SSA, interferon,

combination)

Cytotoxic therapy(streptozotocin + 5-FU, cisplatin + etoposide)

Surgery radio frequency, embolization

ProgressionProgression

Treatment algorithm 2012 ENETS guidelines

PRRT

Progression

Supported by Dr Ramon Salazar

Everolimussunitinib

Clinical trials with new and combined targeted therapies

+ SSA if functional Sd + SSA if functional Sd

Need Resp?High Ki 67?

Modified from Pavel, Salazar et al. Neuroendocrinology Vol. 95:157–176

Thank you!

esmo e-learning: overview on management of neuroendocrine

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